Hypercholesterolemia is an established risk factor in the development of atherosclerosis. Therapeutic agents which control the level of serum cholesterol have proven to be effective in the treatment of coronary artery disease. While agents exist that can modulate circulating levels of cholesterol carrying lipoproteins, these agents have little or no effect on the intestinal absorption of cholesterol. Dietary cholesterol can increase the level of serum cholesterol to levels which place an individual at increased risk for the development or exacerbation of atherosclerosis. Since much of the free or unesterified cholesterol that is absorbed by intestinal mucosal cells must first be esterified by ACAT prior to its incorporation and secretion into the bloodstream in large lipoprotein particles called chylomicrons, inhibition of ACAT can reduce the absorption of dietary cholesterol. In addition, the accumulation and storage of cholesteryl esters in the arterial wall is associated with increased activity of ACAT. Inhibition of the enzyme is expected to inhibit the formation or progression of atherosclerotic lesions in mammals.
There are a limited number of patents in the literature disclosing compounds which are useful as ACAT inhibitors in particular and antiatherosclerotic agents in general. For example, U.S. Pat. No. 4,623,662, issued to De Vries on Nov. 18, 1986, discloses ureas and thioureas as ACAT inhibitors useful for reducing the cholesterol ester content of an arterial wall, inhibiting atherosclerotic lesion development, and/or treatment of mammalian hyperlipidemia. U.S. Pat. No. 4,722,927, issued to Holmes on Feb. 2, 1988, discloses disubstituted pyrimidineamides of oleic and linoleic acids as ACAT inhibitors useful for inhibiting intestinal absorption of cholesterol.
U.S. Pat. No, 4,460,598, issued to Lautenschlager et al. on Jul. 17, 1984, discloses compounds of the formula: ##STR2## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 independently are H, F, Cl, Br, I, alkyl, alkoxy, or CF.sub.3, with the proviso that one or several of R.sup.1 and R.sup.2, R.sup.3 and R.sup.4, or R.sup.5 and R.sup.6 taken together represent methylenedioxy;
R.sup.7 is H, alkali metal ion, alkyl of 1 to 6 carbon atoms, or benzyl; and PA1 n is 0 to 10. PA1 R.sup.1, R.sup.2 and R.sup.3 independently are H, F, Cl, CH.sub.3, CH.sub.3 O, or CF.sub.3 ; PA1 R.sup.4 is H, Na, K, CH.sub.3, CH.sub.3 CH.sub.2, (CH.sub.3).sub.2 CH, CH.sub.3 (CH.sub.2).sub.2, or butyl; PA1 A is C(CH.sub.3).sub.2, CH(CH.sub.2).sub.m CH.sub.3, (CH.sub.2).sub.n, or (CH.sub.2).sub.n-2 CH(CH.sub.3); PA1 m is 0 to 8; and PA1 n is 2 to 10. PA1 R.sup.6 and R.sup.7 independently are H, OH, saturated or unsaturated alkyl, cycloalkyl, or hydroxyalkyl of 1 to 10 carbon atoms, ##STR6## R.sup.8, R.sup.9, R.sup.10, R.sup.11, R.sup.12 and R.sup.13 independently are H, F, Cl, Br, NO.sub.2, CH.sub.3 CONH, OH, alkyl of 1 to 3 carbon atoms, CF.sub.3, and alkoxy of 1 to 3 carbon atoms, with the proviso that R.sup.8 and R.sup.9, R.sup.10 and R.sup.11, or R.sup.12 and R.sup.13 taken together represent methylenedioxy; PA1 R.sup.14 is alkyl of 1 to 2 carbon atoms; PA1 m and n taken together represent a whole number from 0 to 9; PA1 p is 0 to 2; PA1 s is 0 to 2; and PA1 t is 0 or 2. PA1 R.sup.4 and R.sup.5 independently are H, C.sub.6 H.sub.5, or alkyl of 1 to 9 carbon atoms; PA1 R.sup.6 is alkyl, cycloalkyl, or hydroxyalkyl of 1 to 20 carbon atoms, H, alkali metal if X is --COO--, 1-phenethyl, or ##STR9## R.sup.7 is H, OH if X is --CONR.sup.7 --, or alkyl of 1 to 4 carbon atoms; R.sup.8, R.sup.9, R.sup.10 and R.sup.11 are independently H, Cl, F, Br, NO.sub.2, CH.sub.3 CONH, OH, alkyl of 1 to 3 carbon atoms, CF.sub.3, or alkoxy of 1 to 3 carbons, or R.sup.8 and R.sup.9 or R.sup.10 and R.sup.11 taken together represent methylenedioxy; PA1 X is a bond, O, OC(.dbd.O)O, C(.dbd.O)O, CONR.sup.7, OC(.dbd.O), or OC(.dbd.O)NR.sup.7 ; PA1 m and n taken together represent a whole number from 0 to 9; PA1 p is 0 to 2; PA1 s is 0 to 2; and PA1 t is 0 or 2. PA1 R.sup.1 and R.sup.2 can also be taken together as ##STR14## PA1 R.sup.3 is H, C.sub.1 -C.sub.6 alkyl, allyl, benzyl, or phenyl optionally substituted with F, Cl, CH.sub.3, CH.sub.3 O, or CF.sub.3 ; PA1 R.sup.4 is straight chain C.sub.1 -C.sub.8 alkyl optionally substituted with F; C.sub.3 -C.sub.8 branched alkyl, C.sub.3 -C.sub.7 cycloalkyl, C.sub.4 -C.sub.10 cycloalkylalkyl, C.sub.7 -C.sub.14 araalkyl where the aryl group is optionally substituted with 1 to 3 groups selected from C.sub.1 -C.sub.4 alkyl or alkoxy, F, Br, Cl, NH.sub.2, OH, CN, CO.sub.2 H, CF.sub.3, NO.sub.2, C.sub.1 -C.sub.4 carboalkoxy, NR.sup.7 R.sup.8, or NCOR.sup.7 ; C.sub.3 -C.sub.6 alkenyl or alkynyl, C.sub.1 -C.sub.3 perfluoroalkyl, phenyl optionally substituted with 1 to 3 groups selected from C.sub.1 -C.sub.4 alkyl, C.sub.3 -C.sub.8 branched alkyl, C.sub.1 -C.sub.4 alkoxy, F, Br, Cl, NH.sub.2, OH, CN, CO.sub.2 H, CF.sub.3, NO.sub.2, C.sub.1 -C.sub.4 carboalkoxy, NR.sup.7 R.sup.8 or NCOR.sup.7 ; pentafluorophenyl, benzyl optionally substituted with 1 to 3 groups selected from C.sub.1 -C.sub.4 alkyl or alkoxy, F, Br, Cl, NH.sub.2, OH, CN, CO.sub.2 H, CF.sub.3, NO.sub.2, C.sub.1 -C.sub.4 carboalkoxy, NR.sup.7 R.sup.8, or NCOR.sup.7 ; 2-, 3- or 4- pyridinyl, pyrimidinyl, or biphenyl; PA1 R.sup.5 is H, C.sub.1 -C.sub.6 alkyl, or benzyl; PA1 R.sup.6 is C.sub.1 -C.sub.8 alkyl, C.sub.3 -C.sub.8 branched alkyl, C.sub.3 -C.sub.7 cycloalkyl, C.sub.3 -C.sub.8 alkenyl or alkynyl, phenyl optionally substituted with 1 to 3 groups selected from C.sub.1 -C.sub.4 alkyl or alkoxy, F, Br, Cl, NH.sub.2, OH, CN, CO.sub.2 H, CF.sub.3, NO.sub.2, C.sub.1 -C.sub.4 carboalkoxy, NR.sup.7 R.sup.8, or NCOR.sup.7 ; pentafluorophenyl, benzyl optionally substituted with 1 to 3 groups selected from C.sub.1 -C.sub.4 alkyl or alkoxy, F, Br, Cl, NH.sub.2, OH, CN, CO.sub.2 H, CF.sub.3, NO.sub.2, C.sub.1 -C.sub.4 carboalkoxy, NR.sup.7 R.sup.8, or NCOR.sup.7 ; PA1 R.sup.7 and R.sup.8 are selected independently from H or C.sub.1 -C.sub.4 alkyl; PA1 X is S(O).sub.r, O, NR.sup.5, CH.sub.2 ; PA1 A is C.sub.2 -C.sub.10 alkyl, C.sub.3 -C.sub.10 branched alkyl, C.sub.3 -C.sub.10 alkenyl, or C.sub.3 -C.sub.10 alkynyl; PA1 Y is O, S, H.sub.2, NH; PA1 Z is NHR.sup.4, OR.sup.4, or R.sup.4 ; PA1 r is 0-2, PA1 or a pharmaceutically acceptable salt thereof. PA1 R.sup.1 and R.sup.2 are selected independently from C.sub.1 -C.sub.8 alkyl, C.sub.3 -C.sub.8 branched alkyl, C.sub.3 -C.sub.7 cycloalkyl, C.sub.4 -C.sub.10 cycloalkylalkyl, C.sub.7 -C.sub.14 araalkyl, 2-, 3-, or 4-pyridinyl, 2-thienyl, 2-furanyl, phenyl optionally substituted with 1 to 2 groups selected from F, Cl, Br, OH, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkyl, C.sub.3 -C.sub.8 branched alkyl, CH.sub.3 S(O).sub.r, NO.sub.2, or NR.sup.7 R.sup.8 ; or PA1 R.sup.1 and R.sup.2 can also be taken together as ##STR15## where L is O, O(CH.sub.2).sub.m+1 O, or (CH.sub.2).sub.m where m is 0-4. PA1 R.sup.3 is H, CH.sub.3, phenyl; PA1 R.sup.6 is C.sub.1 -C.sub.8 alkyl, C.sub.3 -C.sub.8 branched alkyl, C.sub.3 -C.sub.7 cycloalkyl, phenyl optionally substituted with 1 to 3 groups selected from CH.sub.3, CH.sub.3 O, F, Br, Cl, NH.sub.2, OH, CN, CO.sub.2 H, CF.sub.3, or di(C.sub.1 -C.sub.4)alkylamino; or benzyl optionally substituted with 1 to 3 groups selected from CH.sub.3, CH.sub.3 O, F, Br, Cl, NH.sub.2, OH, CN, CO.sub.2 H, CF.sub.3, or di(C.sub.1 -C.sub.4)alkylamino; PA1 X is S(O).sub.r, CH.sub.2 ; PA1 A is C.sub.2 -C.sub.10 alkyl, C.sub.4 -C.sub.9 branched alkyl. PA1 R.sup.1 and R.sup.2 are selected independently from C.sub.1 -C.sub.8 alkyl, C.sub.3 -C.sub.8 branched alkyl, C.sub.3 -C.sub.7 cycloalkyl, C.sub.4 -C.sub.10 cycloalkylalkyl, C.sub.7 -C.sub.14 araalkyl, 2-, 3-, or 4-pyridinyl, 2-thienyl, or phenyl optionally substituted with 1 to 2 groups selected from F, Br, Cl, C.sub.1 -C.sub.4 alkyl, C.sub.3 -C.sub.8 branched alkyl, CH.sub.3 O, CH.sub.3 S(O).sub.r, NO.sub.2, or di(C.sub.1 -C.sub.4)alkylamino; or PA1 R.sup.1 and R.sup.2 can also be taken together as ##STR16## where L is O or OCH.sub.2 O; R.sup.3 is H; PA1 R.sup.4 is C.sub.1 -C.sub.8 alkyl, C.sub.3 -C.sub.8 branched alkyl, C.sub.3 -C.sub.7 cycloalkyl, C.sub.4 -C.sub.10 cycloalkylalkyl, C.sub.7 -C.sub.14 araalkyl, phenyl substituted with 1 to 3 groups selected from CH.sub.3, F, Cl, CH.sub.3 O, CN; or benzyl optionally substituted with 1 to 3 groups selected from CH.sub.3, CH.sub.3 O, F, Cl, or CN; PA1 R.sup.6 is C.sub.1 -C.sub.8 alkyl or phenyl optionally substituted with 1 to 3 groups selected from CH.sub.3, CH.sub.3 O, F, Cl, or CN; PA1 A is C.sub.4 -C.sub.9 alkyl; PA1 X is S(O).sub.r.
The synthesis and the use of these compounds in the treatment of thromboembolic, inflammatory and/or atherosclerotic diseases is disclosed.
U.S. Pat. No. 4,654,358, issued to Lautenschlager et al. on Mar. 31, 1987, discloses compounds of the formula: ##STR3## wherein k is 0, 1, or 2,
The synthesis and the use of these compounds in the treatment of inflammatory diseases, diseases of lipid metabolism, and/or hyperlipidemic diseases is disclosed.
German Laid Open Application No. DE 3504679, Lautenschlager et al., published Aug. 14, 1986, discloses compounds of the formula: ##STR4## wherein R.sup.1, R.sup.2 and R.sup.3 independently are H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 1 to 6 carbon atoms, or ##STR5## R.sup.4 and R.sup.5 independently are H, C.sub.6 H.sub.5, or alkyl or 1 to 9 carbon atoms;
The synthesis and the use of these compounds in the treatment of thromboembolic, inflammatory, atherosclerotic, and lipid metabolism diseases in general is disclosed.
German Laid Open Application No. DE 3504680, Lautenschlager et al., published Aug. 14, 1986, discloses compounds of the formula: ##STR7## wherein R.sup.1, R.sup.2 and R.sup.3 independently are H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 1 to 6 carbon atoms, or ##STR8## R.sup.1 and R.sup.2 can be taken together with the carbon atoms in the 4 and 5 position of the imidazole ring to represent a carbocyclic five- or six-membered aromatic or partially hydrogenated ring which may be substituted by R.sup.8 or R.sup.9 ;
The synthesis and the use of these compounds in the treatment of thromboembolic, inflammatory, atherosclerotic, and lipid metabolism diseases in general is disclosed.
Durant et al., U.S. Pat. No. 4,228,291, issued Oct. 14, 1980, teaches compounds of the formula: ##STR10## wherein A together with the carbon atom form an unsaturated heterocyclic nucleus which may be an imidazole, pyrazole, pyrimidine, pyrazine, pyridazine, thiazole, isothiazole, oxazole, isoxazole, triazole, thiadiazole, benzimidazole, or 5,6,7,8-tetrahydroimidazol[1,5-a]pyridine ring; X.sub.1 is H, lower alkyl, hydroxyl, trifluoromethyl, benzyl, halogen, amino, or ##STR11## X.sub.2 is H, or when X.sub.1 is lower alkyl, lower alkyl or halogen; k is 0 to 2 and m is 2 or 3, provided that the sum of k and m is 3 or 4; Y is O, S, or NH; E is NR.sub.2 ; R.sub.1 is H, lower alkyl or di-lower alkyl amino-lower alkyl; and R.sub.2 is H, nitro, or cyano. The compounds are said to be antihistamines of the H.sub.2 receptor blocking type, as well as having anti-inflammatory activity.
White, U.S. Pat. No. 4,413,130, Nov. 1, 1983, discloses histamine H.sub.2 receptor antagonists of the formula: ##STR12## where A together with the carbon atom form an unsaturated heterocyclic nucleus which may be an imidazole, pyridine, thiazole, isothiazole, oxazole, isoxazole, pyrazole, triazole, thiadiazole, pyrimidine, pyrazine or pyridazine; X.sub.1 and X.sub.2 may be H, lower alkyl, trifluoromethyl, hydroxyl, halogen, amino, or X.sub.1 and X.sub.2 and at least two of the atoms comprising A may form a further ring; k is 0 to 2 and m is 2 or 3, provided that the sum of k and m is 3 or 4; E is O, S, or NR.sub.2 ; R.sup.1 is H, lower alkyl, acyl, or dialkylaminoalkyl; and R.sub.2 is H, NO.sub.2, CN, alkansulphonyl or arenesulphonyl.
There are no known literature references disclosing the imidazoles of this invention, their use as ACAT inhibitors, or their use to lower cholesterol or in the treatment of atherosclerosis.
The compounds of this invention are very potent ACAT inhibitors. As shown by the data presented below in Table 6, the compounds of this invention inhibit ACAT activity in vitro with at least ten times the potency of any ACAT inhibitors described in the current literature. As shown by the data presented below in Table 8, the compounds of this invention cause a reduction in the serum cholesterol level in cholesterol-fed hamsters. The compounds of this invention are thus expected to be useful in pharmaceutical formulations for the treatment of atherosclerosis. The compounds of this invention have been shown to lower serum cholesterol, and this invention should not be construed as limited to any particular antihypercholesterolemic mechanism of action.